Process for preparing 3-amino-5-(pyridinyl)-2(1H)-pyridinones via N-hydroxy-1,2-dihydro-2-oxo-5-(pyridinyl)-nicotinimidamide by reaction with polyphosphoric acid

ABSTRACT

N-Hydroxy-1-R 1  -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamides or pharmaceutically-acceptable acid-addition salts thereof, useful as cardiotonic agents, are prepared by reacting 1-R 1  -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles with hydroxylamine and are converted by reaction with polyphosphoric acid to the corresponding cardiotonically useful 1-R 1  -3-amino-5-PY-6-R-2(1H)-pyridinones, where R 1  is hydrogen, lower-alkyl and lower-hydroxyalkyl, R is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.

This is a division of application Ser. No. 218,616, filed Dec. 22, 1980and now U.S. Pat. No. 4,305,948, issued Dec. 15, 1981.

CROSS-REFERENCE TO RELATED APPLICATIONS

U.S. patent application Ser. No. 198,461, filed Oct. 20, 1980 and nowU.S. Pat. No. 4,313,951, issued Feb. 2, 1982, discloses as cardiotonicsand intermediates1,2-dihydro-2-oxo-5-(pyridinyl)-6-(lower-alkyl)nicotinonitriles, whichare used herein as intermediates for preparingN-hydroxy-1,2-dihydro-2-oxo-5-(pyridinyl)-6-(lower-alkyl)nicotinimidamides.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 1,2-dihydro-5-(pyridinyl)-2-oxonicotinamidederivatives, their preparation, their cardiotonic use and theirconversion to the corresponding 3-amino-5-(pyridinyl)-2(1H)-pyridinones,also cardiotonics.

(b) Description of the Prior Art

Lesher and Opalka U.S. Pat. Nos. 4,004,012, issued Jan. 18, 1977, and4,072,746, issued Feb. 7, 1978, show as cardiotonic agents3-amino-5-(pyridinyl)-2(1H)-pyridinones and their preparation from thecorresponding 3-carbamyl compounds. Said3-carbamyl-5-(pyridinyl)-2(1H)-pyridinones, alternatively named1,2-dihydro-2-oxo-5-(pyridinyl)nicotinamides, were shown only asintermediates.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention resides inN-hydroxy-1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide (I) orpharmaceutically-acceptable acid-addition said thereof, where R, R₁ andPY are defined below.

A composition aspect of the invention resides in a cardiotoniccomposition for increasing cardiac contractility in a patient, saidcomposition comprising a pharmaceutically-acceptable carrier and, as theactive component thereof, a cardiotonically-effective amount ofN-hydroxy-1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide orpharmaceutically-acceptable acid-addition salt thereof.

In a method aspect, the invention resides in a method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering a medicament comprising apharmaceutically-acceptable carrier and, as the active componentthereof, a cardiotonically-effective amount of N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimamide orpharmaceutically-acceptable acid-addition salt thereof.

In a process aspect the invention comprises reacting 1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile with hydroxylamine toproduce N-hydroxy-1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide (I)and reacting I with polyphosphoric acid to produce 1-R₁-3-amino-5-PY-6-R-2(1H)-pyridinone. Other process aspects comprise eachof the above two steps, namely, the preparation of I and its conversionto 1-R₁ -3-amino-5-PY-6-R-2(1H)-pyridinone.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

In a composition of matter aspect the invention resides inN-hydroxy-1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide havingformula I ##STR1## or pharmaceutically-acceptable acid-addition saltthereof, where R is hydrogen or lower-alkyl, R₁ is hydrogen, lower-alkylor lower-hydroxyalkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinylhaving one or two lower-alkyl substituents. The compounds of formula Iare useful both as intermediates for preparing the correspondingcardiotonically useful 3-amino analogs of I and also as cardiotonicagents, as indicated by standard pharmacological evaluation procedures.Preferred embodiments are those of formula I where PY is 4-or3-pyridinyl, R₁ is hydrogen and R is hydrogen, methyl or ethyl.

A composition aspect of the invention resides in a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, a cardiotonically-effective amount of N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide orpharmaceutically-acceptable acid-addition salt thereof, where PY, R andR₁ have the meanings given above for the compounds of formula I.Preferred embodiments are those compositions where the active componentsare said preferred embodiments of formula I.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering to such patient a composition comprising apharmaceutically-acceptable carrier and, as the active componentthereof, a cardiotonically-effective amount of N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide (I) orpharmaceutically-acceptable acid-addition salt thereof, where PY, R andR₁ have the meanings given above for the compounds of formula I.

In a process aspect the invention comprises reacting 1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile with hydroxylamine toproduce N-hydroxy-1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide (I)and reacting I with polyphosphoric acid to produce 1-R₁-3-amino-5-PY-6-R-2(1H)-pyridinone. Other process aspects comprise eachof the above two steps, namely, the preparation of I and its conversionto 1-R₁ -3-amino-5-PY-6-R-2(1H)-pyridinone. Preferred embodiments of theprocess aspects are those utilizing compounds where PY is 4- or3-pyridinyl, R₁ is hydrogen and R is hydrogen, methyl or ethyl.

The term "lower-alkyl" as used herein, e.g., as one of the meanings of Ror R₁ or as a substituent for PY in formula I, means an alkyl radicalhaving from one to six carbon atoms which can be arranged as straight orbranched chains, illustrated by methyl, ethyl, n-propyl, isopropyl,n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl, and thelike.

The term "lower-hydroxyalkyl", as used herein, e.g., as one of themeanings for R₁ in formula I, means a hydroxyalkyl radical having fromtwo to six carbon atoms and having its hydroxy group and its freevalence bond (or connecting linkage) on different carbon atoms,illustrated by 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl,5-hydroxypentyl, 6-hydroxyhexyl, and the like.

Illustrative of PY in formula I where PY is 4- or 3-pyridinyl having 1or 2 lower-alkyl substituents are the following: 2-methyl-4-pyridinyl,2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl,6-methyl-3-pyridinyl (alternatively named 2-methyl-5-pyridinyl),2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl,2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl,2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl,2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the like.

The compounds of formula I are useful both in the free base form and inthe form of acid-addition salts, and, both forms are within the purviewof the invention. The acid-addition salts are simply a more convenientform for use; and in practice, use of the salt form inherently amountsto use of the base form. The acids which can be used to prepare theacid-addition salts include preferably those which produce, whencombined with the free base, pharmaceutically-acceptable salts, that is,salts whose anions are relatively innocuous to the animal organism inpharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base are not vitiated by side effectsascribable to the anions. In practicing the invention, it is convenientto use the free base form; however, appropriatepharmaceutically-acceptable salts within the scope of the invention arethose derived from mineral acids such as hydrochloric acid, sulfuricacid, phosphoric acid and sulfamic acid; and organic acids such asacetic acid, citric acid, lactic acid, tartaric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like, giving thehydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate,tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid-addition salts of said basic compound (I) are prepared eitherby dissolving the free base in aqueous or aqueous-alcohol solution orother suitable solvents containing the appropriate acid and isolatingthe salt by evaporating the solution, or by reacting the free base andacid in an organic solvent, in which case the salt separates directly orcan be obtained by concentration of the solution.

Although pharmaceutically-acceptable salts of said basic compound (I)are preferred, all acid-addition salts are within the scope of theinvention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a pharmaceutically-acceptable salt by ionexchange procedures.

The molecular structures of the compound of formula I were assigned onthe basis of evidence provided by infrared, nuclear magnetic resonanceand mass spectra, and by the correspondence of calculated and foundvalues for the elemental analysis.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same, as follows.

The preparation of the intermediate 1-R₁-1,2-dihydro-2-oxo-5-PY-6-nicotinonitriles where R is lower-alkyl aredescribed in the next three paragraphs. These intermediatenicotinonitriles are disclosed and claimed as cardiotonics in copendingapplication Ser. No. 198,461 filed Oct. 20, 1980.

The preparation of 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone byreacting PY-methyl lower-alkyl ketone with dimethylformamidedi-(lower-alkyl) acetal is carried out by mixing the reactants in thepresence or absence of a suitable solvent. The reaction is convenientlyrun at room temperature, i.e., about 20°-25° C., or by warming thereactants up to about 100° C., preferably in an aprotic solvent,conveniently hexamethylphosphoramide because of the method used toprepare the PY-methyl lower-alkyl ketone, as noted below in Example A-1.Other suitable solvents include tetrahydrofuran, dimethylformamide,acetonitrile, ether, benzene, dioxane, and the like. Also, the reactioncan be run without solvent, preferably using an excess ofdimethylformamide di-(lower-alkyl)acetal. This procedure is furtherillustrated hereinbelow in Examples A-1 through A-11.

The intermediate PY-methyl lower-alkyl ketones are generally knowncompounds which are prepared by known methods [e.g., as given in Rec.trav. chim 72, 522 (1953); U.S. Pat. No. 3,133,077 (5-12-64); Bull. Soc.Chim 1968, 4132; Chem. Abstrs. 79, 8539h (1973); Chem. Abstrs. 81,120,401a (1974); J. Org. Chem. 39, 3834 (1974); Chem. Abstrs. 87, 6594q(1977); J. Org. Chem. 43, 2286 (1978)].

The reaction of 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone withN-R₁ -α(-cyanoacetamide to produce 1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile is carried out preferably byheating the reactants in a suitable solvent in the presence of a basiccondensing agent. The reaction is conveniently run using an alkalilower-alkoxide, preferably sodium methoxide or ethoxide, indimethylformamide. In practicing the invention, the reaction was carriedout in refluxing dimethylformamide using sodium methoxide.Alternatively, methanol and sodium methoxide or ethanol and sodiumethoxide can be used as solvent and basic condensing agent,respectively; however, a longer heating period is required. Other basiccondensing agents and solvents include sodium hydride, lithiumdiethylamide, lithium diisopropylamide, and the like, in an aproticsolvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene, dioxane,and the like. This procedure is further illustrated hereinbelow inExamples B-1 through B-15.

The intermediate 1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles whereR is hydrogen are known, e.g., U.S. Pat. Nos. 4,004,012 and 4,072,746,noted hereinabove under Description of the Prior Art.

The reaction of 1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles withhydroxylamine to produce N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide by heating the reactants atabout 50° C. to 100° C., preferably at about 60° L C. to 65° C. andpreferably in an appropriate solvent. The reaction was conveniently runin refluxing methanol.

The reaction of N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide with polyphosphoric acid toproduce 1-R₁ -3-amino-5-PY-6-R-2(1H)-pyridinone was carried out byheating the reactants at about 50° C. to 100° C., preferably about 95°C. to 100° C.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. 1-PY-2-(DIMETHYLAMINO)ETHENYL LOWER ALKYL KETONES

A-1. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl methyl ketone--A mixturecontaining 20 g. of (4-pyridinyl)methyl methyl ketone [alternativelynamed 1-(4-pyridinyl)-2-propanone] and 30 cc. of hexamethylphosphoramidewas diluted with 65 ml. of dimethylformamide dimethyl acetal and theresulting mixture was refluxed for 30 minutes. TLC analysis showed asingle spot, thereby indicating completion of the reaction (in anotherrun, the reaction appeared to be complete after 30 minutes at roomtemperature). The reaction mixture was evaporated under reduced pressureusing a rotary evaporator and a pressure of about 15 mm., therebyresulting in a crystalline residue weighing 24 g. The residue waspurified by continuous chromatographic extraction on alumina (about 150g.) using chloroform (recycled by distillation onto the alumina) aseluant. After 1 and 1/2 hours, the extract was heated in vacuo to removethe chloroform, thereby leaving, as a light yellow crystalline material,23.2 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone,alternatively named 4-dimethylamino-2-(4-pyridinyl)-3-buten-2-one.

The above preparation can be carried out using in place ofhexamethylphosphoramide other solvents, e.g., dimethylformamide,acetonitrile or others noted above or in the absence of a solvent;however, hexamethylphosphoramide was conveniently used since(4-pyridinyl)methyl methyl ketone was conveniently prepared as a mixturetogether with hexamethylphosphoramide, as seen by the followingpreparation: To a stirred solution containing 70 ml. of freshlydistilled diisopropylamine and 200 ml. of tetrahydrofuran at 0° C. undernitrogen was added dropwise over 20 minutes 210 cc. of 2.4 Mn-butyllithium in n-hexane and the reaction mixture was stirred forabout 35 minutes at about 0°-5° C. To the cold solution was addeddropwise over a period of 10 minutes 90 ml. of dryhexamethylphosphoramide (no temperature change) and a resulting lightyellow solution was stirred for 15 minutes. To the cold solution at 0°C. was added a solution of 50 ml. of 4-picoline in 150 ml. of drytetrahydrofuran over a 15 minute period and stirring was continued for30 minutes at 0° C. Next, a mixture containing 50 ml. of dry ethylacetate and 150 ml. of tetrahydrofuran was added over a 15 minute period(temperature rose from 0° to about 6° C.) and the resulting mixture wasstirred for 20 minutes at 0° C. The ice bath was then removed andstirring continued for another 90 minutes whereupon the temperature ofthe reaction mixture rose to about 25° C. The reaction mixture was thencooled in an ice bath and to it was added 60 ml. of acetic acid over aperiod of about 90 minutes. The tetrahydrofuran was distilled off usinga rotary evaporator in vacuo. The remaining mixture was diluted with 400ml. of water and the aqueous mixture was extracted successively with two250 ml. portions of isopropyl acetate and three 80 ml. portions ofchloroform. The solvents were distilled off under reduced pressure toyield about 137 g. of a mixture consisting primarily of the desiredproduct and hexamethylphosphoramide. Another run using the samequantities was carried out as above except after the addition of 60 ml.of glacial acetic acid, the mixture was diluted with only 200 ml. ofwater, the phases were separated, and the aqueous phase was extractedwith five 100 ml. portions of chloroform. The chloroform extract waswashed with saline solution and the chloroform was distilled off invacuo. The remaining mixture of the desired ketone andhexamethylphosphoramide was combined with the above 137 g. of the samemixture and the combined mixture was distilled under reduced pressure toyield the following fractions: I. 63 g., b.p. of 110°-112° C. at 4 mm.;II. 59 g. of pale yellow oil, b.p. 113°-115° C. at 3 mm.; and, III. 69g. of pale yellow oil, b.p. 115°-118° C. at 2.5 mm. Examination offraction III by NMR showed it to consist of a 2:3 mixture by weight of(4-pyridinyl)methyl methyl ketone and hexamethylphosphoramide.

Acid-addition salts of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methylketone are conveniently prepared by adding to a mixture of 5 g. of1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone in about 100 ml.of aqueous methanol the appropriate acid, e.g., methanesulfonic acid,concentrated sulfuric acid, concentrated phosphoric acid, to a pH ofabout 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitated salt, e.g., dimethanesulfonate, sulfate,phosphate, respectively. Also, the acid-solution salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities each of 1-(4-pyridinyl)-2-(dimethylamino)ethenylmethyl ketone and the appropriate acid, e.g., lactic acid orhydrochloric acid, to prepare respectively the monolactate ormonohydrochloride salt in aqueous solution.

A-2. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone--A mixturecontaining 87.5 g. of (4-pyridinyl)methyl ethyl ketone [alternativelynamed 1-(4-pyridinyl)-2-butanone] and 160 ml. of hexamethylphosphoramidewas diluted with 100 g. of dimethylformamide dimethyl acetal and theresulting mixture was stirred under nitrogen at room temperature for 45minutes. The methanol formed by the reaction was distilled off in vacuousing a rotary evaporator and the remaining material was distilled underreduced pressure to yield two fractions, one boiling at 45°-80° C. at0.5 mm. and the second at 90°-95° C. at 0.5 mm. After TLC analysisshowed predominantly a single spot for each fraction, the two fractionswere combined (135 g.) and taken up in 600 ml. of chloroform. Theresulting solution was washed with two 300 ml. portions of water and thewater was back extracted with three 100 ml. portions of chloroform. Thecombined chloroform solution was dried over anhydrous sodium sulfate andpurified by continuous extraction chromatography on 300 ml. of aluminausing chloroform (recycled by distillation onto the alumina) as theeluant. The chloroform was distilled off in vacuo to yield a red oilwhich crystallized on standing overnight in an ice bath. The crystallinematerial was dissolved in carbon tetrachloride, cyclohexane was addedand the mixture cooled to yield 64 g. of the resulting yellowcrystalline product, 1-(4-pyridinyl)-2-(dimethylamino)ethenyl ethylketone. Another 11 g. of crystalline product was obtained from themother liquor by continuous extraction chromatography on alumina usingchloroform (recycled by distillation onto the alumina) as the eluant.

The above intermediate (4-pyridinyl)methyl ethyl ketone was obtained ina mixture with hexamethylphosphoramide as follows: To a mixturecontaining 200 ml. of tetrahydrofuran and 70 ml. of diisopropylamineunder nitrogen at 0°-5° C. was added 210 ml. of 2.4 N n-butyllithium inn-hexane and the resulting mixture was stirred for 30 minutes. Next wasadded over a 10 minute period 90 ml. of hexamethylphosphoramide followedby stirring of the mixture for 15 minutes. Then was added over a 15minute period a solution of 48 ml. of 4-picoline in 150 ml. oftetrahydrofuran followed by stirring for 30 minutes at about 0° C. Theice/acetone bath cooling the reaction mixture was replaced with a dryice/acetone bath and to the reaction mixture was added over a 20 minuteperiod a mixture of 75 ml. of ethyl propionate in an equal volume oftetrahydrofuran. The reaction mixture was then allowed to warm up toroom temperature over a period of about 90 minutes and then was warmedat about 35° C. for 30 minutes. The mixture was next cooled in anice/acetone bath and to it was added 60 ml. of glacial acetic acid over30 minutes. The resulting pale yellow suspension was diluted with 200ml. of water. The mixture was extracted with three 150 ml. portions ofethyl acetate and the ethyl acetate extract was back washed with salinesolution. The extract was heated in vacuo to remove the ethyl acetateand the residue was taken up again with ethyl acetate. The solution waswashed with water and then heated in vacuo to remove the ethyl acetatefollowed by heating the residue in vacuo at 50° C. for about 30 minutesto yield 100 g. of pale yellow oil. The pale yellow oil was combinedwith corresponding samples obtained from two additional runs and thendistilled in vacuo to yield a 256 g. fraction, b.p. 85°-105° C. at0.5-1.0 mm. The NMR of this fraction showed it to be a mixture of(4-pyridinyl)methyl ethyl ketone and hexamethylphosphoramide in arespective molar ratio of 1:1.55, that is, 35% or 0.35×256=90 g. of saidketone.

A-3. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone--A mixturecontaining 80 g. of (4-pyridinyl)methyl n-propyl ketone [alternativelynamed 1-(4-pyridinyl)-2-pentanone] and 46 cc. of hexamethylphosphoramidewas diluted with 250 ml. of acetonitrile. To the mixture was added 90ml. of dimethylformamide dimethyl acetal and the resulting reactionmixture was heated on a steam bath for ninety minutes and then distilledunder vacuum at about 2 mm. to remove volatile materials, includingmethanol, acetonitrile and hexamethylphosphoramide. The remainingresidue was diluted with ethyl acetate and washed with water. Thecombined water washings were extracted with five 150 cc. portions ofethyl acetate. The combined ethyl acetate solutions were washed withsaline solution, dried over anhydrous sodium sulfate, filtered andevaporated to dryness. The residue crystallized while standing in afreezer. The crystalline product was slurried with cyclohexane, filteredand dried overnight at 30° C. to produce, as a yellow crystallineproduct, 97 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-propylketone, m.p. 48°-50° C.

The above intermediate (4-pyridinyl)methyl n-propyl ketone was obtainedin a mixture with hexamethylphosphoramide as follows: To a stirredsolution of 70 ml. of diisopropylamine in 200 ml. of tetrahydrofuranunder nitrogen at about 0° C. (use of ice bath) was added 210 cc. of 2.4N n-butyllithium over twenty minutes and the resulting mixture wasstirred for 30 minutes at about 0° C. to the mixture was added withstirring over ten minutes 90 ml. of hexamethylphosphoramide and theresulting mixture was stirred for another ten minutes. Next 45 ml. of4-picoline in 140 ml. of tetrahydrofuran was added dropwise over fifteento twenty minutes. The resulting dark orange-brown solution was stirredat 0° C. for thirty minutes and then treated dropwise over an eighteenminute period a solution consisting of 68 ml. of ethyl butyrate in 68ml. of tetrahydrofuran, the temperature rising from -8° C. to +8° to 10°C. The reaction mixture was removed from the ice bath and allowed towarm up to room temperature for over seventy-five minutes. The reactionmixture was re-cooled and to it was added dropwise over fifteen minutes60 ml. of glacial acetic acid. A pale yellow solid separated, resultingin a suspension. The suspension was diluted with water and extractedwith two 200 ml. portions of ethyl acetate. The ethyl acetate extractwas washed with three 100 ml. portions of saline solution, dried overanhydrous sodium sulfate and evaporated in vacuo to yield 107 g. of amixture consisting primarily of (4-pyridinyl)methyl n-propyl ketone andhexamethylphosphoramide. The mixture obtained in this run was combinedwith corresponding mixtures obtained in two other runs and the combinedmixtures were distilled under vacuum to produce, as the major fraction,b.p. 80°-90° C. at 0.2 mm., a mixture consisting of 80 g. of(4-pyridinyl)methyl n-propyl ketone and 46 g. ofhexamethylphosphoramide.

Following the procedure described in Example A-2 but using a molarequivalent quantity of the appropriate PY-methyl lower-alkyl ketone inplace of (4-pyridinyl)methyl ethyl ketone, it is contemplated that thecorresponding 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketones ofExamples A-4 thru A-11 can be obtained.

A-4. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl methyl ketone using(3-pyridinyl)methyl methyl ketone.

A-5. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl isopropyl ketone using(4-pyridinyl)methyl isopropyl ketone.

A-6. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-butyl ketone using(4-pyridinyl)methyl n-butyl ketone.

A-7. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl isobutyl ketone using(4-pyridinyl)methyl isobutyl ketone.

A-8. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl tert-butyl ketone using(4-pyridinyl)methyl tert.-butyl ketone.

A-9. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-pentyl ketone using(4-pyridinyl)methyl n-pentyl ketone.

A-10. 1-(2-Methyl-4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketoneusing (2-methyl-4-pyridinyl)methyl ethyl ketone.

A-11. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone using(3-pyridinyl)methyl ethyl ketone.

B. 1-R₁ -1,2-DIHYDRO-6-(LOWER-ALKYL)-2-OXO-5-PY-NICOTINONITRILES

B-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile,alternatively named1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile--To amixture containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenylmethyl ketone and 11 g. of α-cyanoacetamide dissolved in 400 ml. ofdimethylformamide was added with stirring 14 g. of sodium methoxide andthe resulting reaction mixture was heated in an oil bath under gentlereflux for one hour. TLC analysis showed no starting material in thereaction mixture which was then concentrated in vacuo on a rotaryevaporator to a volume of about 80 ml. The concentrate was treated withabout 160 ml. of acetonitrile and the resulting mixture was stirred on arotary evaporator with warming until homogeneous and then cooled. Thecrystalline product was collected, rinsed successively with acetonitrileand ether, and dried overnight at 55° C. to yield 28 g. of tancrystalline product, namely, sodium salt of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presenceof cyano being confirmed by IR analysis. An 8 g. portion of said sodiumsalt was dissolved in 75 ml. of hot water, the aqueous solution treatedwith decolorizing charcoal filtered, the filtrate again treated withdecolorizing charcoal and filtered, and the filtrate acidified with 6N-hydrochloric acid by dropwise addition to a pH of 3. The acidicmixture was diluted with ethanol and cooled. The crystalline product wascollected, dried, recrystallized from dimethylformamide-water and driedto produce 3.75 g. of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p., >300°C.

Acid-addition salts of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile areconveniently prepared by adding to a mixture of 2 g. of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40ml. of aqueous methanol the appropriate acid, e.g., methanesulfonicacid, concentrated sulfuric acid, concentrated phosphoric acid, to a pHof about 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitated salt, e.g., dimethanesulfonate, sulfate,phosphate, respectively. Also, the acid-addition salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities each of1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile and theappropriate acid, e.g., lactic acid or hydrochloric acid, to preparerespectively the monolactate or monohydrochloride salt in aqueoussolution.

B-2. 6-Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile,alternatively named2-ethyl-1,6-dihydro-6-oxo-[3,4'-bipyridine]-5-carbonitrile, m.p. 300°C., 11.6 g., was prepared following the procedure described above inExample B-1 using 20 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenylethyl ketone, 8.4 g. of α-cyanoacetamide, 16.2 g. of sodium methoxideand 250 ml. of dimethylacetamide (as solvent in place ofdimethylformamide).

B-3. 1,2-Dihydro-2-oxo-6-n-propyl-5-(4-pyridinyl)nicotinonitrile,alternatively named1,6-dihydro-6-oxo-2-n-propyl-[3,4'-bipyridine]-5-carbonitrile, m.p.232°-234° C., 9.9 g., was prepared following the procedure describedabove in Example B-1 using 85 g. of1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone, 36.5 g. ofα-cyanoacetamide, 50 g. of sodium methoxide and 800 ml. ofdimethylacetamide.

B-4. 1,2-Dihydro-1,6-dimethyl-2-oxo-5-(4-pyridinyl)nicotinonitrile,alternatively named1,6-dihydro-1,2-dimethyl-6-oxo-(3,4'-bipyridine)-5-carbonitrile, m.p.245°-248° C. 32.3 g., was prepared following the procedure describedabove in Example B-1 using 42.5 g. of1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone, 23.5 g. ofN-methyl-α-cyanoacetamide, 6.7 g. of sodium methoxide, 400 ml. ofmethanol and a refluxing period of two hours.

Following the procedure described in Example B-2 but using a molarequivalent quantity of the appropriate 1-PY-2-(dimethylamino)ethenyllower-alkyl ketone in place of 1-(4-pyridinyl)-2-(dimethylamino)ethenylethyl ketone and the appropriate N-R₁ -α-cyanoacetamide, it iscontemplated that the corresponding 1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles of Examples B-5 thru B-15can be obtained.

B-5. 1,2-Dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinonitrile, using1-(3-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone andα-cyanoacetamide.

B-6. 1,2-Dihydro-6-isopropyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl isopropyl ketone andα-cyanoacetamide.

B-7. 6-n-Butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-butyl ketone andα-cyanoacetamide.

B-8. 1,2-Dihydro-6-isobutyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl isobutyl ketone andα-cyanoacetamide.

B-9. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)-6-tert.-butylnicotinonitrile,using 1-(4-pyridinyl)-2-(dimethylamino)ethenyl tert.-butyl ketone andα-cyanoacetamide.

B-10. 1,2-Dihydro-2-oxo-6-n-pentyl-5-(4-pyridinyl)nicotinonitrile, using1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-pentyl ketone andα-cyanoacetamide.

B-11. 6-Ethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl)-2-oxonicotinonitrile,using 1-(2-methyl-4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone andα-cyanoacetamide.

B-12. 6-Ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile, using1-(3-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone andα-cyanoacetamide.

B-13.6-Ethyl-1,2-dihydro-1-(2-hydroxyethyl)-2-oxo-5-(4-pyridinyl)nicotinonitrile,using 1-(4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone andN-(2-hydroxyethyl)-α-cyanoacetamide.

B-14. 1-Ethyl-1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile,using 1-(4-pyridinyl)-2-dimethylamino)ethenyl methyl ketone andN-ethyl-α-cyanoacetamide.

B-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile,using 1-(4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone andN-ethyl-α-cyanoacetamide.

C. N-HYDROXY-1-R₁ -1,2-DIHYDRO-2-OXO-5-PY-6-R-NICOTINIMIDAMIDES

C-1. N-HYDROXY-1,2-DIHYDRO-2-OXO-5-(4-PYRIDINYL)NICOTINIMIDAMIDE,alternatively namedN-hydroxy-1,6-dihydro-6-oxo-[3,4'-bipyridin]-5-carboximidamide--To asolution containing 8.0 g. of sodium hydroxide dissolved in 500 ml. ofabsolute methanol was added with stirring 15.9 g. of hydroxylaminehydrochloride. To the resulting stirred mixture containing precipitatedsodium chloride was added 19.7 g. of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile and the resultingsuspension was refluxed with stirring on a steam bath for forty-threehours. The resulting bright yellow solid that separated was collected,washed with a small quantity of fresh methanol and was then trituratedtwice with water to remove sodium chloride. The remaining product wasdried in a vacuum oven at 90° C. to yield 20.6 g. ofN-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide m.p. 228° C.with decomposition.

Acid-addition salts ofN-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide areconveniently prepared by adding to a mixture of 2 g. ofN-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide in about 40ml. of aqueous methanol the appropriate acid, e.g., methanesulfonicacid, concentrated sulphuric acid, concentrated phosphoric acid, to a pHof about 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitated salt, e.g., dimethanesulfonate, sulfate,phosphate, respectively. Also, the acid-addition salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities each ofN-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide and theappropriate acid, e.g., lactic acid or hydrochloric acid, to preparerespectively the monolactate or monohydrochloride salt in aqueoussolution.

Following the procedure described in Example C-1 but using a molarequivalent quantity of the appropriate 1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile in place of1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile, it is contemplatedthat the corresponding N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamides of Examples C-2 thru C-13can be obtained.

C-2.N-Hydroxy-1,2-dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinimidamide,using 1,2-dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinonitrile.

C-3.N-Hydroxy-1,2-dihydro-6-isopropyl-2-oxo-5-(4-pyridinyl)nicotinimidamide,using 1,2-dihydro-6-isopropyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.

C-4. N-6-n-butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide,using 6-n-butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile.

C-5.N-Hydroxy-1,2-dihydro-6-isobutyl-2-oxo-5-(4-pyridinyl)nicotinimidamide,using 1,2-dihydro-6-isobutyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.

C-6.N-Hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)-6-tert.-butylnicotinimidamide,using 1,2-dihydro-2-oxo-5-(4-pyridinyl)-6-tert.-butylnicotinonitrile.

C-7.N-Hydroxy-1,2-dihydro-2-oxo-6-n-pentyl-5-(4-pyridinyl)nicotinimidamide,using 1,2-dihydro-2-oxo-6-n-pentyl-5-(4-pyridinyl)nicotinonitrile.

C-8.N-Hydroxy-6-ethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl)-2-oxonicotinimidamide,using 6-ethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl)-2-oxonicotinonitrile.

C-9.N-Hydroxy-6-ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinimidamide,using 6-ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile.

C-10.N-Hydroxy-6-ethyl-1,2-dihydro-1-(2-hydroxyethyl)-2-oxo-5-(4-pyridinyl)nicotinimidamide,using6-ethyl-1,2-dihydro-1-(2-hydroxyethyl)-2-oxo-5-(4-pyridinyl)nicotinonitrile.

C-11.N-Hydroxy-1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinimidamide,using 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.

C-12.N-Hydroxy-1-ethyl-1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinimidamide,using 1-ethyl-1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.

C-13.N-Hydroxy-1,6-diethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide,using 1,6-diethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile.

D. 1-R₁ -3-AMINO-5-PY-6-R-2(1H)-PYRIDINONES

D-1. 3-Amino-5-(4-pyridinyl)-2(1H)pyridinone--A mixture containing 2.0g. of N-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide and 16g. of polyphosphoric acid was stirred with a glass rod until a stiffpaste was obtained. The mixture was then heated on a steam bath withoccasional stirring for 12 hours and then allowed to stand at roomtemperature over the weekend. The reaction mixture was warmed a littleto soften the viscous mixture which was then treated with about 100 ml.of water and mixed well to dissolve the excess polyphosphoric acid. Ayellow solid material that separated was collected, suspended in freshwater and to the suspension was added ammonium hydroxide until themixture was distinctly alkaline. The solid which did not dissolve wascollected, washed with a little water and dried in a vacuum oven at 90°C. to produce 0.9 g. of 3-amino-5-(4-pyridinyl)-2(1H)pyridinone, m.p.293°-295° C. with decomposition. This product was identical with asample of amrinone, that is, 3-amino-5-(4-pyridinyl)-2(1H)pyridinonewhich had been prepared from its corresponding 3-carbamyl precursor asshown in U.S. Pat. No. 4,072,746.

Following the procedure described in Example D-1 but using a molarequivalent quantity of the appropriate N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide in place ofN-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide, it iscontemplated that the corresponding 1-R₁-3-amino-PY-6-R-2(1H)-pyridinones of Examples D-2 thru D-12 can beobtained.

D-2. 3-Amino-6-methyl-5-(3-pyridinyl)-2(1H)-pyridinone, usingN-hydroxy-1,2-dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinimidamide.

D-3. 3-Amino-6-isopropyl-5-(4-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-1,2-dihydro-6-isopropyl-2-oxo-5-(4-pyridinyl)nicotinimidamide.

D-4. 3-Amino-6-n-butyl-5-(4-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-6-n-butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide.

D-5. 3-Amino-6-isobutyl-5-(4-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-1,2-dihydro-6-isobutyl-2-oxo-5-(4-pyridinyl)nicotinimidamide.

D-6. 3-Amino-5-(4-pyridinyl)-6-tert.-butyl-2(1H)pyridinone, usingN-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)-6-tert.-butylnicotinimidamide.

D-7. 3-Amino-6-n-pentyl-5-(4-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-1,2-dihydro-2-oxo-6-n-pentyl-5-(4-pyridinyl)nicotinimidamide.

D-8. 3-Amino-6-ethyl-5-(2-methyl-4-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-6-ethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl)-2-oxonicotinimidamide.

D-9. 3-Amino-6-ethyl-5-(3-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-6-ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinimidamide.

D-10.3-Amino-6-ethyl-1-(2-hydroxyethyl)-5-(4-pyridinyl)-2(1H)pyridinone,usingN-hydroxy-6-ethyl-1,2-dihydro-1-(2-hydroxyethyl)-2-oxo-5-(4-pyridinyl)nicotinimidamide.

D-11. 3-Amino-1-ethyl-6-methyl-5-(4-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-1-ethyl-1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinimidamide.

D-12. 3-Amino-1,6-diethyl-5-(4-pyridinyl)-2(1H)pyridinone, usingN-hydroxy-1,6-diethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide.

The usefulness of the compounds of formula I or salts thereof ascardiotonic agents is demonstrated by their effectiveness in standardpharmacological test procedures, for example, in causing a significantincrease in contractile force in the Isolated Cat Atria and PapillaryMuscle Procedure and in causing a significant increase in cardiaccontractile force in the Anesthetized Dog Procedure with low or minimalchanges in heart rate and blood pressure. Detailed descriptions of thesetest procedures appear in U.S. Pat. No. 4,072,746, issued Feb. 7, 1980.

When tested by the above-noted Isolated Cat Atria and Papillary MuscleProcedure, the compounds of formula I when tested at doses of 100 or 300μg./ml., were found to cause a significant increase, that is, greaterthan 25%, in papillary muscle force and a significant increase, that is,greater than 25%, in right atrial force, while causing a lowerpercentage increase (about one-half or less than the percentage increasein right atrial force or papillary muscle force) in right atrial rate;for example, N-hydroxy-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide(Example C-1), when tested by said procedure was found to cause a 25%increase in each of papillary muscle force and right atrial force at 100μg/ml and 48% and 43% increases respectively in papillary muscle forceand right atrial force at 300 μg/ml.

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, a cardiotonically-effective amount of N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide of formula I orpharmaceutically-acceptable acid-addition or cationic salt thereof. Theinvention also includes within its scope the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering to such patient a composition comprising apharmaceutically-acceptable carrier and, as the active componentthereof, a cardiotonically-effective amount of said N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide (I) orpharmaceutically-acceptable acid-addition or cationic salt thereof. Inclinical practice said compound or salt thereof will normally beadministered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions canalso contain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc and the like.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater and liquid paraffin. Besides inert diluents such compositions canalso contain adjuvants, such as wetting and suspending agents, andsweetening, flavouring, perfuming and preserving agents. According tothe invention, the compounds for oral administration also includecapsules of absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilising, preserving,wetting, emulsifying and dispersing agents.

They can be sterilized, for example by filtration through abacteria-retaining filter, by incorporation of sterilising agents in thecompositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentages of active components in the said composition and methodfor increasing cardiac contractility can be varied so that a suitabledosage is obtained. The dosage administered to a particular patient isvariable, depending upon the clinician's judgement using as thecriteria: the route of administration, the duration of treatment, thesize and condition of the patient, the potency of the active componentand the patient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing the best judgement on the patient's behalf.

We claim:
 1. The process which comprises reacting 1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile with hydroxylamine toproduce N-hydroxy-1-R₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide andreacting said N-hydroxy nicotinimidamide with polyphosphoric acid toproduce 1-R₁ -3-amino-5-PY-6-R-2(1H)-pyridinone, where R is hydrogen orlower-alkyl, R₁ is hydrogen, lower-alkyl or lower-hydroxyalkyl, and PYis 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkylsubstituents.
 2. The process which comprises reacting N-hydroxy-1-R₁-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide with polyphosphoric acid toproduce 1-R₁ -3-amino-5-PY-6-R-2(1H)pyridinone, where R is hydrogen orlower-alkyl, R₁ is hydrogen, lower-alkyl or lower-hydroxyalkyl, and PYis 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkylsubstituents.